Substantial biologic evidence indicates that microRNAs may play crucial role in development of cancer by regulating their target genes that control biological processes, such as cell cycle, cell proliferation, differentiation, and apoptosis. However, the importance of common inherited variants in microRNA-related genes and their interactions with constitutional host factors and UV exposure history in causing skin cancer is largely unknown. We propose to examine in detail the associations of genetic variants in microRNA-related genes with the risk of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) simultaneously in a nested case-control study within the Nurses Health Study (219 melanoma cases, 286 SCC cases, 300 BCC cases, and 874 matched controls). This innovative work will move this field forward, by evaluating common variants using complementary approaches, i.e. to evaluate putative functional SNPs and to choose tag- SNPs to test for associations of unknown common functional variants with skin cancer risk. In addition, we will also assess the interactions between genetic variants in these genes and constitutional host factors and UV exposure history on skin cancer risk. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohort, including cohort characteristics, quality of design, high follow-up rate, rigor in prospective host risk factor assessment, and high response rate of retrospective questionnaires. Our study will also take advantage of the previously confirmed cases of the three types of skin cancers, stored blood and DNA samples, as well as previously collected information on host risk factors and UV exposure history. This research will contribute to the scientific basis for identifying high-risk individuals for skin cancer and providing individualized risk management strategies.